This proposal is for a three year renewal of a cooperative agreement between NIMH and participating centers at Johns Hopkins University, Indiana University and Washington University at St. Louis. The Intramural Research Program of NIMH participates under a separate mechanism. The goal of the collaboration is to assemble a large set of multiplex families with Bipolar Affective Disorder for genetic linkage studies. We have proceeded to develop a systematic ascertainment scheme to identify families with a Bipolar I (BPI) proband and a BPI or Schizoaffective Bipolar (SA/BP) first-degree relative. Additional living and available relatives are required to ensure the maximum informativeness of the sample. Non-systematically ascertained families are accepted into the study if they have four or more closely related affected individuals. A new structured interview, the Diagnostic Interview for Genetic Studies (DIGS) was developed, field-tested, and assessed for intrasite and intersite reliability. A companion instrument, the Family Interview for Genetic Studies (FIGS) was also developed as part of this program. A central Data Management Center (DMC) archives diagnostic information, and a National Cell Repository stores genetic material. At this point, 115 families have been identified at the four sites. About 65% of these have been systematically ascertained. These families include 495 persons with major affective disorder among 1656 living members. Eight hundred thirty- five subjects have been directly interviewed, and 767 persons have had blood samples sent to the Cell Repository for transformation. Simulation studies show that the existing sample is capable of detecting a single locus under conditions of 50% heterogeneity, and that the projected sample (220 families with 2200 cell lines) will likely detect a locus responsible for illness in only 25% of the families. This renewal proposes the completion of the already ascertained families, the continuing ascertainment of new families until the projected total is reached, and the clinical follow-up of participants to ensure the maximum phenotypic validity of the sample. The follow-up study will enable course of illness to be included as a nosological variable, provide incident cases and newly informative branches of pedigree and reduce the loss of power resulting from instability of diagnosis.